A recently discovered mechanism of cell injury, the "Poly (ADP-ribose) Synthetase (PARS) pathway" has been implicated in the pathogenesis of neuronal injury. Triggered by oxidant-induced DNA single strand breaks, PARS catalyzes an energy-consuming polymerization of ADP-ribose, resulting in NAD depletion, inhibition of glycolysis and mitochondrial respiration, and the ultimate reduction of intracellular high-energy phosphates, which culminates in neuro injury. The applicants are developing novel classes of compounds with neuroprotective potential. In this proposal, we present evidence that PARS knockout animals, and animals treated with various classes of novel PARS inhibitors PJ34 are resistant against brain trauma. We also present preliminary data with PJ34, a novel, water-soluble, ultrapotent PARS inhibitor. Inotek's mid-term intention is to develop an ultrapotent PARS inhibitor of the PJ class as a drug for the treatment of neural injury associated with various forms of CNS trauma. The specific aim of the present proposal is to synthesize novel PARS inhibitors, screen them for efficacy and toxicity in vitro and in vivo, and then to perform definitive in vivo studies with selected lead candidates in murine models of brain and spinal cord trauma. In vivo studies will also define the dose-response relationship, frequency of administration, and the therapeutic window. Finally, a single lead compound candidate will be selected, which will undergo formal preclinical safety and pharmacokinetic studies. By the end of a 2-year project, the applicants will be prepared to undertake a human Phase I safety trial with a selected ultrapotent PARS inhibitor with promise of efficacy in CNS trauma. PROPOSED COMMERCIAL APPLICATION: The annual domestic impact of brain and spinal cord trauma on the health care market is estimated at >$750 million. The worldwide market is four times larger. Given the absence of a specific, safe, and convenient existing therapy, Inotek anticipates market acceptance to be achieved rapidly, at high levels of penetration, and with a high sustained price point ($1000 per patient). Estimated worldwide revenues after market entry and maturation (ca. 4 years after FDA approval)=$750 million (annual).